Abstract

To evaluate the efficacy of SGLT2 inhibitors as an add-on therapy along with
stricter lifestyle modification in Asian Indian type 2 diabetes mellitus (T2DM)
patients with inadequate glycemic control despite receiving an optimum dose
of at least 4 oral antidiabetic drugs (OADs).

A retrospective analysis of data of 808 T2DM patients being treated with
an SGLT2 inhibitor (Dapagliflozin, Empagliflozin or Canagliflozin) as an add-on
drug in patients with inadequate glycemic control despite receiving optimum
doses of at least any four OADs(metformin, sulphonylureas, pioglitazone, DPP4
Inhibitors, alpha-Glucosidase Inhibitors) and who preferred not to initiate insulin.

The average age of the patients included was 51.63 years (SD ± 9.88).
57.7% were males. Average weight was 81.95±16.08 kg. Mean duration of diabetes
was 34.08±39.04 months. The mean baseline fasting plasma glucose was 198.21
± 38.21 mg/dl and mean post prandial plasma glucose was 264.22 ± 45.22 mg/
dl. The baseline HbA1c was 8.92 ± 1.47 %. Total 87.4 % of the cases responded
to addition of SGLT2 inhibitors during a mean follow-up period of 6 months.

The mean weight reduction at 6 months of therapy was -3.03± 01.84 kg that is
3.8 % decrease from baseline (p=0.001).The response in age group < 55 years
was 90.9 %, whereas in ≥55 years, it was 82.2% (p=0.001). The males responded
more (91.0%) compared to females (82.5%) (p=0.001). Those with BMI < 23.5 kg/
m2 had marginally higher but insignificant response of 93.0% as compared to
87.1% in patients with high a BMI (≥23.5 kg/m2) (p=0.253). Patients with < 5years
duration of diabetes responded better (91.8%) as compared to patients with a
≥ 5 years of diabetes (85.4%).

SGLT2 inhibitors are effective in achieving desired glycemic goals
even when used as a fifth add-on drug along with strict lifestyle modification in
patients with inadequate glycemic control despite receiving an optimum dose
of at least 4 oral antidiabetic drugs (OADs). SGLT2 inhibitors can be effectively
used at any stage of diabetes.

Introduction

According to International Diabetes
Federation (IDF), India has second
largest number of people living with
diabetes worldwide (69.2 million) after
china (109.6 million). It is predicted that
by 2040, India will have approximately
123.5 million diabetes patients; which makes up 10.7% of total adult
population aged 20-79 years.1

Type 2 diabetes mellitusis characterized by progressive beta‑cell
failure.2 Most patients are not able to
maintain good glycemic control on
dual, triple or quadruple therapy with
oral anti‑diabetic drugs (OADs) for
prolonged periods and will ultimately
require insulin. ADA 2017 guidelines
recommend that a patient, on failing to
achieve HbA1c targets with a maximum
of three OADs must be initiated with
insulin therapy.3 However, with the
advent of new OAD’s whose mechanism
of action is independent of beta cell
function; this treatment paradigm may
be challenged.

Insulin treatment has many issues
including patient noncompliance,
negative outlook and treating
physician’s uncertainty to initiate
insulin. Barriers to initiation or
intensification of insulin therapy exist
which include risk of hypoglycemia and
adverse effects such as weight gain.4 In
addition, proper storage conditions are
required for insulin, especially during
travel and fluctuating temperatures.
In cases where the patients prefer to
avoid initiation of insulin, adding
another OAD in lieu of insulin offers an
attractive alternative. The availability
of newer classes of OADs have widened
the scope and possibility of such a
treatment plan. These drugs act by
different and often complementary
mechanisms, addressing different
pathophysiological processes that
perpetuate hyperglycemia.5 SGLT2
inhibitors are the newest class of oral
anti diabetic agents, licensed in India
for the treatment of T2DM since 2012.
SGLT2 inhibitors currently available in
India are Dapagliflozin, Empagliflozin
and Canagliflozin.

There are very few studies available
which have looked at the benefits
of using multiple oral anti diabetic
agents (triple or quadruple therapy)
with complementary mechanisms of
action.6-8 In addition, patients who
refuse to initiate insulin are now
more receptive and committed to
follow diet, exercise and other lifestyle
interventions strictly in their desire to
avoid insulin initiation.

According to our knowledge, the
current study is the first of its kind to
evaluate the efficacy of the currently
available SGLT2 inhibitors as an add-on
therapy along with stricter lifestyle
modification in Asian Indian T2DM
patients who were treated with at least
4 OADs and failed to attain glycaemic
control.

Methods

A retrospective observational
study was carried out in patients with
T2DM who were being treated and
regularly visiting the Diabetes Specialty
Clinic, Mumbai. Patients with poor
glycemic control despite receiving
optimum doses of at least any four
OADs (metformin, sulphonylureas,
pioglitazone, DPP4 Inhibitors or alpha-
Glucosidase Inhibitors) were treated
with any one of the SGLT2 inhibitor
(Dapagliflozin, Empagliflozin or
Canagliflozin) as an add-on drug. The
treatment regimen was decided during
consultation.

Patient’s weight, fasting plasma
glucose (FPG), post prandial glucose
(PPG) and HbA1c , was regularly
assessed during routine clinic visits. All
clinical parameters were electronically
recorded. At each visit to the clinic,
patients were motivated to strictly
adhere to the suggested diet, exercise
and life style modifications by the
treating physician, dietician and diabetic
educator. At each visit compliance to
both drugs and adherence to lifestyle
were recorded.

A total of 808 patients who met the
inclusion criteria were considered for
the final analysis. Glycemic control
was defined by FPG level of ≤130
mg/dl and PPG level of ≤180 mg/dl.
Changes in patient’s weight, HbA1c,
post prandial glucose (PPG) and
fasting Plasma glucose (FPG) before
and after 6 months of SGLT2 inhibitor
treatment were recorded and analysed.
Statistical calculations were performed
with SPSS software. Statistical tests
(Student’s t test and Chi square test) were considered significant if P-value
was < 0.05 at confidence interval of 95%.

Results

A total of 808 patients meeting the
inclusion criteria were selected for this
study. Out of 808, 57.7% (n=466) were
male and 42.3 % (n=342) were females.
Patient population had a mean age
of 51.63 years (SD ± 9.88) and a mean
weight of 81.95 kg (SD ± 16.08). The
mean duration of diabetes was 34.08
months (SD ± 39.04) (Table 1).

The percentage of patients on preexisting
OADs such as Sulphonylureas,
Metformin , DPP4 inhibitors ,
Pioglitazone and / or Alpha Glucosidase
Inhibitors (AGIs) were as follows in
Figure 1.

The baseline treatment regimen
included any of the four OAD’s prior
to starting on SGLT2 inhibitors. SGLT2
inhibitor therapy was commenced soon
after quadruple OAD therapy failure
to maintain target blood glucose levels
(FPG level of ≤130 mg/dl and PPG
level of ≤180 mg/dl). The mean time for
follow up was of 6 months. Out of total
808 patients, 87.4% (n=706) responded
to the addition of SGLT2 inhibitors as
a fifth drug and were able to achieve
glycemic control of FPG ≤130 mg/dl and
PPG≤180 mg/dl. Only 12.6 % (n=102)
failed to achieve target glycemic levels
(Table 2).

The FPG, PPG and weight were
analysed initially at baseline and then
at each visits after starting add on
SGLT2 therapy. The Mean FPG and
PPG before adding of SGLT2 inhibitor
were 198.21 ± 38.21 mg/dl and 236.9 ±
29.5 mg/dl respectively, which were
reduced to 134.57 ± 33.65 mg/dl and 184.94 ± 38.34 mg/dl. There was a
statistically significant reduction from
baseline of mean FPG (-63.65 mg/dl,
P =0.001) and PPG (-79.28 mg/dl, P
=0.001) (Table 3). The mean HbA1c was
8.92% at baseline and after addition
of SGLT2 inhibitor, the mean HbA1c
showed a significant fall of -1.63% (SD±
0.99) to 7.29 % (SD ± 1.15)(p=0.001).
The mean baseline weight was 81.03
kg (SD± 16.73) .With the addition of an
SGLT2 inhibitor, the subsequent mean
reduction from the baseline in weight
was of 3.03 kg (P =0.001) i.e. 3.8 % from
baseline (Table 3).

The time required for patient to
achieve their glycemic target levels
varied significantly. 40.1% of the
patients required < 2 months to control
diabetes. 40.8% patients were able
to achieve glycemic targets in 2-4
months. 9.3% patients required 4-6
months while 9.8 % patients required
> 6 months to control diabetes (Table
4). Approximately 80% of patients
responded favorably at 4 months of
add-on therapy.

90.9% of patients belonging to age
group < 55 years responded to the
treatment which was significantly more
as compared to 82.2% of patients whose
age was ≥ 55 years (p=0.001). 91.0%
of the male patients responded to the
treatment which was significantly more
as compared to 82.5% of the female
patients (p=0.001). 90.8% of the patients
who had a history of diabetes for < 5
years significantly responded to add-on
treatment compared to 85.9% of the
cases who had diabetes for ≥ 5 years.
(p=0.011). It was observed that male
patients, young patients and those with
lesser duration of diabetes responded
better to SGLT2 inhibitor treatment.

Discussion

In this study we have found that
addition of an SGLT2 inhibitor as a
fifth drug to the treatment regimen of
patients uncontrolled on 4 OAD’s can
achieve good glycemic control and can
delay the initiation of insulin therapy.
It is important to note that the patients
were motivated to adhere to a stricter
lifestyle.

The American Diabetes Association/
European Association for the Study of
Diabetes Joint Task Force recommends
triple OAD therapy in some patients
where agents with complementary
mechanisms of action should be used.10
However there are no studies which
have reported the efficacy of SGLT2
inhibitors as an add-on to triple or
quadruple oral combinations. There is
only one case study in which SGLT2
inhibitor has been added as an add-on
to triple combination therapy of
metformin, glimepiride, and sitagliptin.
After three months of therapy, the
patient HbA1c was 6.9% with fasting
and postprandial values of 97 and 138
mg/dL, respectively. Additionally, a
weight loss of 1.9 kg was documented.11
OAD’s such as sulphonylureas and
pioglitazone as well as insulin therapy often result in weight gain. Hence, any
add-on therapy that can cause weight
loss is worth taking into consideration.

Our study has shown significant
reduction in HbA1c using SGLT2
inhibitor as the fifth drug along
with strict lifestyle modification.
The improvement was found to be
statistically significant where mean
FPG and PPG levels reduced by -63.65
mg/dl and -79.28 mg/dl respectively
(P =0.001) and majority of the patients
(87.4%) were able to control FPG and
PPG levels to target levels. The mean
HbA1c showed a significant fall of
-1.63%, which can be a synergistic
effect of multiple OADs working on
different pathophysiologic mechanisms
of type 2 diabetes along with stricter
adherence to lifestyle modification. The
synergistic effects of two OADs, which
work on different pathophysiologic
mechanisms of type 2 diabetes, have
already been studied and have shown
synergistic HbA1c reduction beyond
simple addition.

The current study also did emphasize
on st r ict adherence to l i festyle
modification in study population,
who were highly motivated due to
their desire to avoid insulin initiation.
In current study, addition of an SGLT2
inhibitor was able to reduce mean
weight by 3.03 kg from baseline, which
may have further helped in reducing
insulin resistance and ultimately
superior HbA1c reduction. In addition,
almost 80% patients were able to
control their diabetes within 4 months
of treatment, out of which around 40 %
had achieved goal in initial 2 months.
Our study reflects real life experience
and demonstrates that addition of
SGLT2 inhibitors as a fifth drug along
with strict lifestyle modification will
help patients control their diabetes for
a prolonged period, delaying insulin
initiation.

This study has some limitations
because of its retrospective nature.
Other important features, such as patient compliance and side effects’
profile, could not be assessed in the
present analysis. However, they do
not significantly affect the importance
of this study.

Conclusion

Patients with type 2 diabetes
who require further improvement in
glycaemic control despite the being
on 4 OADs, SGLT2 inhibitor as a fifth
drug can be considered. They are highly
efficacious when added as fifth drug
along with strict lifestyle modification
and can effectively reduce HbA1c and
weight. They act similarly in Obese
as well as Non-Obese patients. They
can be effectively used at any stage
of diabetes and can delay insulin initiation in Type 2 diabetes patients
not controlled on multiple OADs.

Inzucchi SE, et al. Management of hyperglycemia in type 2
diabetes, 2015: a patient-centered approach: update to a
position statement of the American Diabetes Association
and the European Association for the Study of Diabetes.
Diabetes Care 2015; 38:140-9.

Inzucchi SE, et al. Management of hyperglycemia in type 2
diabetes: a patient-centered approach: position statement
of the American Diabetes Association (ADA) and the
European Association for the Study of Diabetes (EASD).
Diabetes Care 2012; 35:1364-79.

Kelwade J, et al, How many oral antidiabetic drugs before
insulin? Indian Journal of Endocrinology and Metabolism
2017; 21:249-250.